1. Field of the Invention
The present invention relates to novel benzamidine compounds which exhibit an activated blood coagulation factor X (hereinafter sometimes to be abbreviated as FXa) inhibitory activity. The present invention also related to a method of producing such compounds, intermediates useful for producing such compounds, and uses of such a benzamidine compound. The present invention also relates to a low-molecular weight FXa inhibitor, particularly the use of a low-molecular weight FXa inhibitor having a short half-life in blood, for an extracorporeal blood circuit and the like.
2. Discussion of the Background
Extracorporeal blood circulation is an artificial blood circulation through a blood circuit constructed outside the body. Generally, by the extracorporeal blood circulation, the blood is circulated in a circuit from a body via an extracorporeal artificial blood flow tube to an apparatus for a given treatment, for example, an artificial heart lung apparatus, blood purifying device and the like, and then into the body. An extracorporeal blood circulation treatment is sometimes required during a blood purification therapy such as hemodialysis, blood filtration, hemodialysis filtration, plasma exchange, and the like, a heart-lung bypass during open-heart operation and the like. As the blood purification device, a dialyzer and the like are typically mentioned.
When the blood is in contact with a foreign substance, the intrinsic blood coagulation cascade is generally activated, and the blood is finally coagulated and loses flowability. An extracorporeal blood circuit consisting of artificial blood flow tubes and various apparatuses, which is used for extracorporeal blood circulation is a foreign substance, and the blood coagulates upon contact therewith. Therefore, a treatment to prevent blood coagulation in the extracorporeal blood circuit by some means is needed.
Conventionally, anticoagulants such as unfractionated heparin, low-molecular-weight heparin and the like are used for the prevention of thrombus in the extracorporeal blood circuit.
However, unfractionated heparin cannot be used for patients with a high risk of bleeding since, it has a risk of creating a propensity toward hemorrhage due to its thrombin inhibitory activity in addition to the FXa inhibitory activity. Low-molecular-weight heparin is a pharmaceutical agent that inhibits FXa more selectively as compared to thrombin by a chemical treatment of heparin, and is free of a thrombin inhibitory activity. Thus, low-molecular-weight heparin shows a low tendency of causing bleeding, and has been used for patients having a tendency of bleeding. On the other hand, however, since low-molecular-weight heparin has a long disappearance half-life, hemostasis is difficult when the bleeding symptom is observed.
Furthermore, some serine protease inhibitors also have an anticoagulant action. For example, nafamostat mesilate is used for some extracorporeal blood circulations such as hemodialysis and the like. Since nafamostat mesilate has a short disappearance half-life in the body, it is also used for patients with a bleeding lesion. However, nafamostat mesilate does not have a strong inhibitory activity against FXa and thrombin, and shows a weak anticoagulant effect.
As mentioned above, all the pharmaceutical agents have problems yet to be solved, and there is a demand for a more effective and safe pharmaceutical agent.
Patients with an extracorporeal circuit face the problem of blood coagulation only when the circuit is used. Thus, the situation often varies from that of patients requiring continuous prevention of blood coagulation. It has not been assumed heretofore that a selective low-molecular weight FXa inhibitor with a short half-life in blood can be used safely and conveniently as an anticoagulant for the prevention of blood coagulation in an extracorporeal blood circuit, and that the treatment of and attention to hemostasis necessary after the completion of the extracorporeal blood circulation can be clearly reduced.
As a benzamidine compound that exhibits an anticoagulation activity based on a selective FXa inhibitory action, the compounds described in WO98/31661 and WO99/64392 are known. However, these compounds are clearly structurally different from the compound of the present invention which contain an ester structure in the molecular main chain.